A wealth of evidence exists in support of the concept that the steroid hormone estrogen (E2) provides key ontributions to the etiology of breast cancer. Recently, we have shown a novel mechanism by which estrogen could also promote tumor growth and metastasis in cancer cells that do not express estrogen receptors (both ERa and ER(3). Despite the lack of ER expression in the carcinoma cells, we showed that ncreasing the levels of circulating estrogens is sufficient to promote systemic angiogenesis throughout the host, as well as the formation and progression of ER-negative cancers. Additionally, we showed that systemic enhancement of neo-angiogenesis due to estrogen treatment is accompanied by the recruitment of bone marrow-derived cells into the growing tumor mass, including immune macrophages and mesenchymal cells. In fact, the bone marrow cells from estrogen-treated animals promote ER-negative tumor growth. We have now recently characterized some of the bone marrow-derived cells that are mobilized and recruited to sites of angiogenesis and tumor growth in response to estrogen. The mobilization of very early haematopoietic progenitor cells in response to estrogen in an ERadependent manner, as well as the presence of specialized subpopulations of bone-marrow derived monocytes/macrophages and myofibroblasts under pathological conditions, suggest that these cells might important for neo-angiogenesis, lymphangiogenesis and promotion of tumor growth. In this proposal, will examine the specific hypothesis that bone marrow mobilized cells home to sites of inflammation/wound healing, angiogenesis and/or tumor growth and differentiate under specific growth factor microenvironments into cell types that support vascular tube formation and tumor growth. To test this hypothesis, we propose the following specific aims: Aim 1 will determine whether estrogen affects angiogenesis and tumor promotion through the estrogen receptor alpha (ERa) while Aim 2 will investigate the biology and mechanism of action of the estrogen-responsive bone marrow cells recruited to tumors and sites of angiogenesis. The role of estrogen expression by cells other than the breast carcinoma cells remains mechanistically understudied. In particular, bone marrow inflammatory cells, endothelial and lymphatic endothelial cells all express estrogen receptors but their response to the steroid hormone in disease states has not been investigated. This work combined with the improved endocrine therapies under development could provide a molecular and. pca-clinicaL foundation foe the, USB. af specific, anti-estrogen, therapies in. the treatment of all breast cancers.